Acrofacial Dysostoses (Nager Syndrome, Miller Syndrome and the SF3B4 Spectrum)

A class of malformation syndromes that combine a Treacher Collins-type mandibulofacial dysostosis with limb defects: preaxial in Nager syndrome and in the Rodríguez form (SF3B4, autosomal dominant), postaxial in Miller syndrome (DHODH, autosomal recessive), and rare forms with other genes or no known gene; it includes mandibulofacial dysostosis with microcephaly (EFTUD2), a neighbouring spliceosomopathy with thumb anomalies in about one third of patients.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition of the class

The acrofacial dysostoses are congenital syndromes in which a mandibulofacial dysostosis, that is, a developmental abnormality of the structures derived from the first and second pharyngeal arches (malar bone, maxilla, mandible, eyelids and pinna), is associated with limb malformations [1, 49]. The face resembles that of Treacher Collins syndrome, and what separates the subtypes is mainly the topography of the limb defect: in Nager syndrome the defect is preaxial, on the side of the radius and thumb, and in Miller syndrome it is postaxial, on the side of the ulna and fifth finger [39, 50]. Orphanet groups these entities in the clinical group “acrofacial dysostosis” (ORPHA:364574), and OMIM describes Nager syndrome as the prototype of the group [1, 30]. Bernier and colleagues called it the archetype of the class when they identified the responsible gene in 2012 [42].

1.2. Nager syndrome and the Rodríguez form

Nager and de Reynier recognised the entity in 1948, in a patient with a face similar to that of Treacher Collins syndrome and radial limb defects, although OMIM and Zhao and Yang attribute the probable first description to Slingenberg, in 1908 [1, 35, 51]. By 1993 McDonald and Gorski had gathered 76 published cases; Smith's Recognizable Patterns of Human Malformation now counts more than 100 [1, 35]. For decades it was debated whether inheritance was dominant or recessive: there was father-to-son transmission in two families (Aylsworth and colleagues, 1987 and 1990), but also pairs of affected siblings with clinically normal parents (Chemke and colleagues, 1988; Hecht and colleagues, 1987), and in 1987 Opitz went as far as proposing that the syndrome was an “anomaly” of heterogeneous causes [1]. In 1990 Rodríguez and colleagues described three siblings with a lethal form, presumed recessive, with severe mandibular hypoplasia, upper limb phocomelia, absent scapulae and absent fibulae [28, 35]. The identification of heterozygous SF3B4 variants in the Rodríguez form, including in one of the original siblings, led to it being considered the severe end of the Nager spectrum and to familial recurrence being attributed to gonadal mosaicism [21, 40, 52].

1.3. Miller syndrome

Genée published an “extensive form of mandibulofacial dysostosis” in 1969, and Wiedemann described another case in 1973; in 1979 Miller and colleagues brought together six patients, four from the literature, and defined the postaxial acrofacial dysostosis syndrome [4, 41]. Donnai and colleagues reviewed 10 cases in 1987 and established autosomal recessive inheritance [4]. In 2010 Ng and colleagues sequenced the exomes of four patients from three families and found biallelic variants in DHODH, the gene for dihydroorotate dehydrogenase; it was the first Mendelian disease of unknown cause solved by exome sequencing [23, 41, 50].

1.4. Identification of the genes and reclassifications

The Nager syndrome gene was identified in 2012 by the FORGE Canada consortium and the Centers for Mendelian Genomics of the US National Institutes of Health: loss-of-function variants in SF3B4, a component of the spliceosome, explained 20 of 35 families [42]. Petit and colleagues and Czeschik and colleagues confirmed haploinsufficiency as the main cause and showed that some patients with a clinical diagnosis have no variant in this gene [22, 53]. The Cincinnati type, linked to POLR1A, was defined in 2015 in three patients [24]. Other entities described as acrofacial dysostoses remain without a gene: the Catania type (Opitz, 1993; second family in 1996), the Palagonia type (1997) and the Kennedy-Teebi type (2004) [25, 26, 49]. Richieri-Costa-Pereira syndrome, described in Brazilian patients, was attributed in 2014 to repeat expansions in the 5′ untranslated region of EIF4A3 [11]. Weyers syndrome keeps the historical name of “acrofacial dysostosis”, but is an ectodermal dysplasia with postaxial polydactyly, allelic to Ellis-van Creveld syndrome (EVC, EVC2), without mandibulofacial dysostosis [54].

The 2023 revision of the Nosology of Genetic Skeletal Disorders adopted dyadic nomenclature, which joins the phenotype to the gene (for example, “EFTUD2-related mandibulofacial dysostosis with microcephaly”), and places these conditions in the group of craniofacial dysostoses [12, 55]. The distinction between mandibulofacial and acrofacial dysostosis is clinical and depends on the presence of limb defects; for this reason mandibulofacial dysostosis with microcephaly, which has thumb anomalies in some patients, has been proposed as an acrofacial dysostosis by some authors [12].

1.5. Scope of the class and neighbouring entities

The entities of the class are Nager syndrome (with the Rodríguez form), Miller syndrome, the Cincinnati type, the Catania, Palagonia and Kennedy-Teebi types and Richieri-Costa-Pereira syndrome; the first two account for almost all the clinical literature. Treacher Collins syndrome, craniofacial microsomia and Robin sequence share mandibulofacial dysostosis or micrognathia, but not the limb defects, and enter the differential diagnosis in section 6. Thauvin-Robinet-Faivre syndrome has been associated with Nager syndrome in some indexes through coincidence of terms, but OMIM and Orphanet assign it to the FIBP gene, with recessive inheritance, and classify it as an overgrowth syndrome; its clinical characterisation appears in section 3.6, separate from the class [7, 56, 57]. Mandibulofacial dysostosis with microcephaly (EFTUD2), on the border between the mandibulofacial and acrofacial dysostoses, is described in subsections 1.6, 2.9, 3.7, 4.5, 5.9, 6.4, 7.15, 8.6, 9.6, 10.3, 10.4 and 11 [12, 14].

1.6. Mandibulofacial dysostosis with microcephaly (Guion-Almeida type)

Guion-Almeida and colleagues, from the Hospital for Rehabilitation of Craniofacial Anomalies of the University of São Paulo, in Bauru, described in 2006 a syndrome with growth retardation and intellectual disability, mandibulofacial dysostosis, microcephaly and cleft palate; in 2009 they published mother-to-son transmission, and in the same year Wieczorek and colleagues delineated the entity as distinct from Treacher Collins syndrome [58–60]. In 2012 Lines and colleagues sequenced the exomes of four unrelated patients and found heterozygous EFTUD2 variants or deletions in all of them, later confirmed in eight more; it was the first multiple malformation syndrome attributed to a defect of the major spliceosome [61]. In the same year, Gordon and colleagues showed that EFTUD2 haploinsufficiency causes a syndromic oesophageal atresia, in patients previously classified as Feingold syndrome, CHARGE syndrome or oculo-auriculo-vertebral spectrum with oesophageal atresia [62].

Voigt and colleagues used EFTUD2 to explain two familial entities published as distinct, the oto-facial syndrome with midline malformations (two sisters, interpreted as recessive) and a syndrome with oesophageal atresia, hypoplasia of the zygomatic complex, microcephaly, cup-shaped ears, heart disease and intellectual disability in a mother and her two children; they documented the first case of germline mosaicism and proposed reclassifying the entity as an acrofacial dysostosis, because 12 of 35 patients (34%) had thumb anomalies [14]. The descriptive term “mandibulofacial dysostosis with microcephaly” is synonymous with the eponym “mandibulofacial dysostosis, Guion-Almeida type” [12]. Inclusion among the acrofacial dysostoses is a clinical distinction, based on the limb anomalies, and not a pathophysiological one; the 2023 Nosology kept the entity in the group of craniofacial dysostoses with the dyadic designation EFTUD2-related mandibulofacial dysostosis with microcephaly (Guion-Almeida type) [12, 55]. It shares with Nager syndrome the mechanism, loss of function of a spliceosome component, and the Treacher Collins-type face, and is distinguished by microcephaly, intellectual disability and extracranial malformations [12, 63].

2. Molecular Genetics and Pathophysiology

2.1. Common mechanisms: spliceosomopathies and ribosomopathies

The acrofacial dysostoses with a known gene fall into three mechanisms. The first is dysfunction of the spliceosome, the complex that removes introns from pre-mRNA: Nager syndrome (SF3B4), mandibulofacial dysostosis with microcephaly (EFTUD2), Richieri-Costa-Pereira syndrome (EIF4A3), Burn-McKeown syndrome (TXNL4A) and cerebro-costo-mandibular syndrome (SNRPB) belong to this group [33, 42, 63]. The second is deficient ribosome biogenesis, shared by Treacher Collins syndrome (TCOF1, POLR1B, POLR1C, POLR1D) and the Cincinnati type (POLR1A); disruption of ribosomal pre-RNA transcription mainly affects neural crest cells, which form the craniofacial mesenchyme [24, 64]. The third is partial deficiency of de novo pyrimidine synthesis in Miller syndrome (DHODH) [23, 65]. In all cases a universal cellular process fails selectively in tissues with intense proliferation during embryogenesis, such as the pharyngeal arches and limb buds [37, 65, 66].

2.2. SF3B4 and Nager syndrome

SF3B4 is located at 1q21.2, has six exons and encodes the SAP49 protein, of 424 amino acids [46, 67]. SAP49 is a subunit of the SF3B subcomplex of the U2 snRNP: it binds pre-mRNA in a region of about 29 nucleotides near the branch point, interacts with SF3B2 through its RNA recognition domain and is required for assembly of spliceosome complex A; it also participates in the minor spliceosome, which removes U12-type introns [15, 67]. It also has a described role in bone morphogenetic protein (BMP) signalling, inhibiting BMP-mediated osteochondral differentiation [22, 35]. The gene is expressed in the forelimb and hindlimb buds of the mouse embryo at early stages [46]. In cellular, zebrafish, Xenopus and mouse models, loss of SF3B4 causes preferential skipping of AT-rich, GC-poor exons, alters the expression of genes required for neural crest cell survival, proliferation, migration and specification and activates oxidative stress and the p53 pathway [66].

The disease mechanism is haploinsufficiency. In the discovery cohort, 18 different variants explained 20 of 35 families (57%), almost all frameshift [42]; in subsequent series, all variants found predicted null alleles (nonsense, frameshift, loss of the initiator methionine and splice variants) [22, 53]. ClinGen classifies SF3B4 haploinsufficiency as definitively established, which excludes a dominant-negative effect as the main mechanism [67]. A synonymous variant in exon 3, c.417C>T p.(Gly139=), is listed as pathogenic in ClinVar, and Cassina and colleagues demonstrated, using a hybrid minigene, that a synonymous exon 3 variant creates a cryptic splice site and behaves as a hypomorphic allele in a family with three affected members and a highly variable phenotype [68, 69]. Deletions of the whole gene or of several exons (for example, exons 3 to 6) have been detected by microarray, including in prenatal diagnosis [46, 70].

The following table presents recurrent or historically relevant variants normalised in VariantValidator on the MANE transcript NM_005850.5 (GRCh38) [16].

In the review by Ulhaq and colleagues (24 articles, 84 patients, 9 of them with the Rodríguez form), 76% had an SF3B4 variant; 35 distinct variants, 64% frameshift, 20% in exon 3 and a hotspot in exon 1 (12%) [43]. Among the 64 patients with a variant, 55 had Nager and 9 the Rodríguez form; by type, 64% of variants were frameshift, 19% nonsense and 17% eliminated the initiation methionine (the article's figure legend gives 65% and 18%), and the two hotspots were c.1A>G (8 patients) and c.1060dupC (6 patients) [43]. The article's abstract states that there was no significant genotype-phenotype association, but the full text shows some nominally significant differences in multiple comparisons: spine and chest defects were more frequent with exon 2 variants (3 of 4 patients; p = 0.005); ear canal stenosis was more frequent with frameshift variants (76.3%) than with nonsense variants (16.7%; p = 0.0004); upper limb anomalies were more frequent with frameshift variants (97.4%) than with loss of the initiation methionine (66.7%; p = 0.016); and patients with variants predicted to be targets of nonsense-mediated mRNA decay had more upper limb anomalies (96% versus 66.7%; p = 0.022) [43]. Congenital heart disease was more frequent with variants in exons 2 (50%) and 3 (29.4%), without statistical significance (p = 0.162), and there were no differences between carriers of c.1A>G and c.1060dupC [43, 46]. Of the 18 lethal cases gathered, 9 had a frameshift variant [43]. These are data from a compilation of published cases, with groups of 4 to 50 patients, publication bias towards severe cases and no overall correction for the 18 features tested, so these associations are exploratory. In the series of Czeschik and colleagues, the only significant difference between patients with and without a variant was the greater frequency of midface hypoplasia or retrusion in the former (p = 0.045) [1].

Expressivity is highly variable, even within the same family: Petit and colleagues identified mildly affected parents only after the diagnosis of a severely affected child or fetus [1, 22]. Weinbaum and colleagues described a four-generation family in which lower eyelid ptosis, sparse lower eyelashes and cartilaginous tags between the antitragus and the lobule appeared to be minimal expressions [1]. A patient with a loss-of-function variant in SF3B4 was referred for developmental and growth delay, without acrofacial dysostosis or limb defect [73]. Rare variants in spliceosome genes, including SF3B4, have also been found in 2.7% of 224 patients with non-syndromic orofacial cleft, as a possible susceptibility factor [74].

2.3. Genetic heterogeneity of Nager syndrome

Between 24% and 43% of patients with a clinical diagnosis of Nager syndrome have no variant in SF3B4, depending on the series [42, 43, 53]. Patients without a variant are, for the most part, indistinguishable from the others [22]. One of the SF3B4-negative patients in the discovery cohort had a nonsense variant in EFTUD2 and microcephaly, which led to reclassification as mandibulofacial dysostosis with microcephaly [1]. A balanced translocation t(X;9)(p22.1;q32) in a patient with Nager syndrome pointed to the 9q32 region, where ZFP37 and, in 2025, PTBP3 were proposed as candidates: in Xenopus embryos, depletion of Ptbp3 reproduces the hypoplastic craniofacial cartilages of embryos lacking Sf3b4, and ptbp3 expression increases in sf3b4-null embryos; no patients with PTBP3 variants have yet been described [1, 75]. A 1q12-q21 deletion has been described in a patient with Nager syndrome, severe aortic stenosis and bronchial stenosis [1]. In the series of Chummun and colleagues, one of the nine patients had an X;9 translocation [76].

2.4. DHODH and Miller syndrome

DHODH is located at 16q22.2 and encodes dihydroorotate dehydrogenase, a flavoenzyme anchored to the outer face of the inner mitochondrial membrane that catalyses the fourth step of de novo pyrimidine synthesis: it oxidises dihydroorotate to orotic acid, using ubiquinone as the electron acceptor; orotate is then converted to uridine monophosphate by UMP synthase [23, 77]. Saudubray refers to this reaction as a “catabolic pathway”, but it belongs to the biosynthetic pathway [23, 78].

The disease results from partial, not complete, deficiency. Rainger and colleagues tested 11 missense variants by complementation in auxotrophic yeast and by in vitro enzymatic assay: all reduced activity, 7 with discordant results between the two assays, and in all patients the genotype predicted significant residual activity [65]. The Dhodh, Cad and Umps genes, of the same pathway, are strongly expressed in the pharyngeal arches and limb buds of the mouse embryo, suggesting a local and temporary need for pyrimidine synthesis in these tissues [65]. Other disorders of pyrimidine synthesis, such as hereditary orotic aciduria due to UMP synthase deficiency, do not cause malformations [23]. The malformation pattern of Miller syndrome resembles that of methotrexate embryopathy, and leflunomide, a DHODH inhibitor, causes limb and craniofacial defects in mice when given during pregnancy [23, 78]. The exact mechanism remains unclear; disturbances of fibroblast growth factor (FGF) signalling and of the NF-κB/Sonic hedgehog pathway have been proposed [23, 78]. The optic neuropathy observed in a French family led to speculation about a relationship with the mitochondrial function of DHODH, without exclusion of a second genetic cause in the OPA8 interval of chromosome 16 [6].

In the founding article, 11 different variants were found in 6 families (10 missense and 1 indel with frameshift); all parents tested were carriers and no variant was de novo [23]. The 2025 systematic review found 12 variants in the 8 confirmed cases in the literature (11 missense, 1 frameshift), with p.(Arg135Cys) in 5 patients and p.(Arg346Trp) in 2 [36]. In the French cohort all patients had missense variants in the catalytic domain, 4 families in compound heterozygosity and 3 in homozygosity; these were the first homozygotes described, contradicting the earlier hypothesis that homozygosity was incompatible with the disease [6]. There is no mutational hotspot and no established genotype-phenotype correlation, and the most severe case in the cohort (a fetus) was compound heterozygous for two missense variants [6].

2.5. POLR1A and the Cincinnati type

POLR1A (2p11.2) encodes RPA194, the largest, catalytic subunit of RNA polymerase I, which transcribes the 47S ribosomal pre-RNA, precursor of the 18S, 5.8S and 28S RNAs [18, 47]. Heterozygous variants cause the Cincinnati type, with dominant inheritance; in zebrafish, loss of polr1a disrupts ribosome biogenesis and causes p53-dependent cell death, with a deficit of neural crest-derived skeletal precursors [24]. Smallwood and colleagues described 17 more patients with 12 unique variants and showed, in an in vitro allelic series, different effects of each variant on ribosomal RNA synthesis and nucleolar morphology; conditional deletion of Polr1a in mouse neural crest, second heart field and forebrain precursors caused apoptosis and malformations in each lineage, which explains the association of craniofacial, cardiac and neurological anomalies [37]. Biallelic POLR1A variants cause another disease, hypomyelinating leukodystrophy 27, autosomal recessive and without dysostosis (for example p.Thr642Asn in homozygosity) [47, 79, 80]. Zygosity thus defines the phenotype and the recurrence risk [47].

2.6. EIF4A3 and Richieri-Costa-Pereira syndrome

Richieri-Costa-Pereira syndrome is due to repeat expansions in the CG-rich 5′ untranslated region of EIF4A3, which encodes an RNA helicase of the exon junction complex [11, 19]. In Brazilian controls, 97% of alleles have 5 to 12 repeats; patients are homozygous for a 16-repeat allele or compound heterozygous for 16- and 15-repeat alleles, and one patient had a 14-repeat allele in trans with the missense variant c.809A>G p.(Asp270Gly) [19]. This type of allele requires methods targeting the non-coding region (section 5).

2.7. Differential diagnosis genes with a related mechanism

EFTUD2 (17q21.31) encodes the U5-116 kDa GTPase of the spliceosome; heterozygous variants, mostly de novo, cause mandibulofacial dysostosis with microcephaly, with high penetrance and variable expressivity [12]. TXNL4A (18q23), also a component of the U5 snRNP, causes Burn-McKeown syndrome through biallelic variants that almost always include one of two 34-base-pair deletions in the promoter; these deletions are hypomorphic and relatively frequent in the population (45 heterozygotes and 1 homozygote for the type 1 deletion among 3343 healthy individuals), and complete loss of the gene is presumably lethal [33].

2.8. Penetrance, expressivity and modifiers

In Nager syndrome penetrance appears high, but expressivity ranges from the lethal Rodríguez form to parents identified only after a child's diagnosis [22, 40]. No genetic modifiers are known. In Miller syndrome there is intrafamilial variability, with discordant features between siblings [6]. A father carrying a DHODH variant had a history of postaxial polydactyly, and it was not established whether this was a heterozygous manifestation or an independent finding [81]. Ng and colleagues suggested that functional polymorphisms in pyrimidine synthesis genes might modify susceptibility to methotrexate embryopathy, a hypothesis not tested [23].

2.9. EFTUD2 and mandibulofacial dysostosis with microcephaly

EFTUD2 (17q21.31) encodes U5-116 kDa, a 974-amino-acid GTPase that is part of the U5 small nuclear ribonucleoprotein particle (snRNP), present in both the major and minor spliceosomes [12, 38]. The yeast orthologue, Snu114p, is required for dissociation of the U4 and U6 RNAs during spliceosome activation and for disassembly and recycling of the subunits after catalysis; in the U4/U6.U5 tri-snRNP it bridges the helicases Brr2p and Prp8p, and its similarity to the ribosomal elongation factor EF-2 suggests a GTP-dependent conformational change [12, 27]. In the nucleus, EFTUD2 forms a complex with PRPF8, SNRNP200 and SNRNP40, which PRPF6, DDX23, CD2BP2 and TXNL4A join; variants of TXNL4A and EFTUD2 cause craniofacial malformations, whereas those of PRPF8 and SNRNP200, of the same complex, cause retinitis pigmentosa [82].

The variant spectrum (missense, nonsense, frameshift, splice site and partial or whole-gene deletions) is consistent with haploinsufficiency [12, 61]. The tissue specificity of a ubiquitous protein has been studied in animal models. In zebrafish, loss of eftud2 causes apoptosis of neural progenitors through p53 activation, secondary to defective splicing [12, 82]. The heterozygous mouse does not reproduce the phenotype and the homozygote is non-viable, but homozygous loss restricted to neural crest cells (Wnt1-Cre transgene) produces brain and craniofacial malformations, with skipping of exon 3 of Mdm2 and p53 activation; a p53 inhibitor improved craniofacial development in this model, and p53-independent pathways and an endoplasmic reticulum stress response have also been described [82]. EFTUD2 deficiency reduces the proliferation and maturation of human calvarial osteoblasts and chondrocytes in vitro [38]. These data are preclinical and have no therapeutic translation.

In the 2016 update, which gathered 107 patients from 94 families, the 83 distinct EFTUD2 alterations were 7 large deletions (of the whole gene or several exons), 16 frameshifts, 12 nonsense, 32 splice site, 1 small deletion or duplication, 14 missense and 1 intronic change proposed to create a new donor site; among the 76 point variants, missense variants were 18%, nonsense 38% and splice variants 43% [27]. The substitution p.(Arg262Trp), at a conserved residue of the GTP-binding site, is recurrent (three unrelated families), and four other missense variants alter basic surface residues, potentially involved in protein-protein interactions [27]. In May 2025 the EFTUD2 LOVD database listed 111 pathogenic or likely pathogenic variants and ClinVar 171 [38]. 17q21.31 microdeletions that include EFTUD2 and contiguous genes may add signs or worsen the intellectual disability [12, 62].

GeneReviews does not recognise genotype-phenotype correlations [12]. An analysis of 156 patients from 40 articles found no overall correlation, but described more severe manifestations in Asian patients and an association between heart disease and canonical splice site variants; these are data from published cases, with selection bias, and the result is exploratory [86]. Penetrance is high and expressivity variable: two mothers without mosaicism and of normal intelligence, each with two affected children, had only a unilateral zygomatic cleft and facial asymmetry, in one case, and mild asymmetry with a preauricular tag, in the other [12]. Huang and colleagues knew of no proven case of non-penetrance with an unequivocally pathogenic variant; the only apparent case was a paternally inherited deep intronic change, with no clinical description of the parent and no RNA study [27]. No allelic disorders are known [12].

3. Clinical Spectrum and Manifestations by System

3.1. Nager syndrome

Face and skull. The frequencies gathered in Smith are: malar hypoplasia in 97%, downslanting palpebral fissures in 92%, micrognathia in 89%, partial or total absence of the lower eyelashes in 81% and cleft palate in 65%; the nasal root is high [35]. Coloboma of the lower eyelid has been described, but is less frequent than in Treacher Collins syndrome: in the comparison of molecularly confirmed cases in the 2025 review, lower eyelid coloboma was not reported in patients with Nager syndrome, versus 59.8% in Treacher Collins syndrome [36, 39]. The mandible is very short, retrognathic and posteriorly rotated; in three Finnish children assessed at 3–4 years the ramus height was, on average, less than one third of that of controls, the soft palate was absent in all and there was condylar ankylosis or very limited mouth opening [34]. Ankylosis of the temporomandibular joint (TMJ) may be congenital or arise after mandibular distraction osteogenesis [46, 67]. Occasionally there is cleft lip, macrostomia, Robin sequence, velopharyngeal insufficiency, oligodontia, hypoplasia of the larynx or epiglottis and absent epiglottis [35]. Agenesis of permanent teeth (2 to 10 teeth) was present in the three Finnish children, with a complete primary dentition [34].

Ear and hearing. Some ear anomaly is present in 93%: low-set, posteriorly rotated pinnae, preauricular tags and atresia of the external auditory canal [35]. Conductive hearing loss, usually bilateral, affects 88% in Smith and 95% in the Oxford Desk Reference; in the molecularly confirmed cases gathered in 2025 hearing loss was reported in 71.4% [35, 36, 50].

Airway and feeding. Micrognathia is the main cause of morbidity and mortality. Almost half of patients with a confirmed variant had critical airway problems in the neonatal period and required tracheostomy (44%); gastrostomy is frequent, prematurity is common and perinatal mortality is around 20%, linked to the airway [35]. In the neonatal database of US children's hospitals (2010–2023), the 11 newborns with Nager syndrome had median Apgar scores of 2 and 6 at 1 and 5 minutes, intubation at birth in 91%, tracheostomy in 72.7% and in-hospital mortality of 27.3%, versus 1.9% in the 103 newborns with Treacher Collins syndrome and 7.2% in the 4210 children with other forms of micrognathia admitted to neonatal intensive care; median length of stay was 43 days [87]. In a two-centre series (Adelaide and Rotterdam), 7 of 9 patients (77.8%) had obstructive sleep apnoea, severe in 5 [76]. At 3–4 years, the tracheostomised Finnish children still had a severely obstructed or closed lower pharyngeal airway, with a wide nasopharynx [34]. Dysphagia is attributed to mandibular hypoplasia, the TMJ, reduced mouth opening, cleft palate and absent epiglottis [51].

Upper limbs. Upper limb defects are present in 100% of cases in Smith: hypoplasia or aplasia of the thumb, with or without aplasia of the radius, proximal radioulnar synostosis with limited elbow extension and short forearms [35]. Proximal radioulnar synostosis was found in 16 of 19 cases studied by McDonald and Gorski [1]. Triphalangeal or duplicated thumbs, syndactyly, clinodactyly and camptodactyly may occur [35, 39]. In severe cases there is shortening of the humerus, humero-radio-ulnar synostosis, shoulder girdle malformation and phocomelia [39]. The dysmelia is almost symmetrical [39].

Lower limbs and axial skeleton. The lower limbs are generally normal or have minor changes, such as metatarsus varus, short or broad halluces, hypoplastic or overlapping toes and clubfeet; more than half of the patients of Czeschik and colleagues, with or without a variant, had foot and toe anomalies [1, 35, 39]. Hip dislocation, hypoplastic first rib, scoliosis and cervical and vertebral anomalies have also been described [35].

Heart and other organs. Congenital heart defects include ventricular septal defect, patent ductus arteriosus and tetralogy of Fallot; Petit and colleagues found them in 3 of 13 molecularly confirmed patients, and Bellanger and colleagues described the third case of Nager syndrome with tetralogy of Fallot (variant c.1229delC) [1, 39, 88]. Other occasional associations are diaphragmatic eventration or hernia (a 22-week fetus with a splice variant and a newborn who died from pulmonary hypoplasia), genitourinary anomalies (renal agenesis, duplex ureter, vesicoureteric reflux, cryptorchidism, epispadias), Hirschsprung disease and urticaria pigmentosa [15, 35, 72]. A man with Nager syndrome died at 50 years of heart failure due to complete atrioventricular block [1].

Development. Intelligence is normal in the great majority; speech and language delays are related to hearing loss, cleft palate and mandibular structure [35]. Intellectual disability, microcephaly, hydrocephalus due to aqueduct stenosis and polymicrogyria are occasional [35]. The European consensus considers that there is no direct causal relationship between the genetic alteration and cognitive deficits, but that hearing loss, sleep apnoea with intermittent hypoxia, visual and speech problems and reflux increase the risk of acquired deficits [44].

Frequencies with molecular confirmation. The review by Ulhaq and colleagues, which gathered patients published up to June 2021 with molecular testing, allows 64 patients with an SF3B4 variant to be compared with 20 without a variant; none of the 18 features differed significantly between the two groups [43]. Frequencies lower than those in Smith reflect retrospective collection of reports with incomplete clinical description, in which absence of mention does not equate to absence of the sign.

Source: Ulhaq and colleagues (2023), Table 1 [43].

Neoplasms. A case of synchronous bilateral breast cancer has been described in a 31-year-old woman with Nager syndrome, with no germline variant on a 29-gene panel; somatic inactivation of SF3B4 in breast tumours suggests a suppressor role, but a single case does not establish increased risk [89].

3.2. Rodríguez form

The Rodríguez form is characterised by severe mandibular hypoplasia, upper limb phocomelia with oligodactyly, absent fibula, hypoplasia of the scapulae and ischia, 11 pairs of ribs, clubfeet, hypertelorism, microtia and visceral malformations (arhinencephaly, abnormal lung lobation, heart defects); most die in the perinatal period from respiratory failure [3, 28]. The three original siblings died in the neonatal period [28]. Bone Dysplasias illustrates three cases: a 30-week stillborn with hypoplastic scapulae, narrow chest, very short humeri with humeroradial ankylosis and absent thumbs; a newborn with hooked clavicles and “Y”-shaped bones formed by fusion of hypoplastic humerus, radius and ulna; and another with severe micrognathia and right humeroradial ankylosis, all with normal lower limbs [39]. A long-surviving patient had phocomelia with preaxial and postaxial defects, fibular agenesis and rib and shoulder girdle anomalies [52]. Drivas and colleagues described a newborn with bilateral humeroradial synostosis and absent or hypoplastic ulna, with an intermediate phenotype, and concluded that the Rodríguez form is not necessarily lethal with intensive medical care [40].

3.3. Miller syndrome

Face. In the systematic review of 44 cases (35 families; only 8 with molecular confirmation), craniofacial hypoplasia was present in 88.6%, micrognathia in 75.0% and midface hypoplasia in 72.7% [36]. Orofacial clefts (77.3%) were mainly isolated cleft palate (65.9%; complete in 43.2%, soft palate only in 18.2%, submucous in 4.5%), with cleft lip and palate in 11.4% [36]. There were eyelid anomalies in 70.5%: slanting fissures in 43.2% (downslanting 29.5%, upslanting 13.6%), ectropion in 31.8%, upper or lower colobomas in 20.5%, blepharophimosis and sparse medial lower eyelashes in 18.2% each [36]. The ears were abnormal in 63.6%, mainly cup-shaped (45.5%) and low-set (29.5%); microtia is less typical than in Nager syndrome [36]. Smith adds sparse eyebrows, long philtrum, short upturned nose with a high columella and, sometimes, a vertical bony cleft in the malar bone [41]. In the French cohort, micrognathia or retrognathia was present in 8 of 10, cleft lip and/or palate or bifid uvula in 7 of 10, and ectropion and palpebral cleft were described in only 1 of 10, so their absence does not exclude the diagnosis [6]. With age, ectropion and facial asymmetry may worsen and the face becomes more triangular, with thin lips; micrognathia tends to improve [4, 41].

Limbs. Limb defects are present in all cases: hands in 95.5%, feet in 90.9% and forearms in 52.3%; the 5th ray is absent or malformed in the hands in 88.6% and in the feet in 81.8% [36]. In the French cohort all patients lacked the postaxial fingers and 80% lacked the postaxial toes; sometimes the 4th and 5th rays are missing [6]. Associated features are hypoplasia or aplasia of the ulna and fibula, mesomelic shortening, radioulnar synostosis (4 of 9 in the French cohort; 15.9% in the review), bony syndactyly of the ulnar or fibular rays, camptodactyly, carpal or tarsal fusions and “Y”-shaped metacarpals [6, 36]. Preaxial involvement (hypoplasia of the radius, thumb or tibia) was observed in 6 of 9 patients in the French cohort and thumb anomalies in 38.6% of cases in the review, so the distinction between preaxial and postaxial forms is not absolute [6, 36]. Radiologically there are triangular terminal phalanges, cone-shaped epiphyses of the middle phalanges of the toes, supernumerary vertebrae and rib defects [41, 81].

Other systems. Accessory or dysplastic nipples (4 of 9 in the French cohort) [6, 41]. Congenital heart defects were reported in 15.9% of the review (VSD 9.1%, ductus arteriosus 4.5%, ASD and tricuspid regurgitation 2.3% each) and in 4 of 10 French patients (ASD in 3, ductus arteriosus in 2, VSD in 1) [6, 36]. There are vertebral anomalies in 27.3% (pectus excavatum 22.7%, scoliosis 6.8%), genital anomalies in 15.9% (only in males: cryptorchidism and micropenis), and gastrointestinal, central nervous system and renal anomalies in less than 10% [36]. Intestinal malrotation, gastric volvulus, pyloric stenosis, anal prolapse and absent hemidiaphragm have been described [4, 41]. Neonatal cholestasis may progress to persistent liver disease; a 4-year-old boy had early hepatic complications, considered atypical [41, 45]. Optic neuropathy affected 3 of 4 members of a consanguineous French family, and two children from different families had facial naevus simplex [6].

Hearing, growth and development. Hearing loss was reported in 18.2% of the review (normal in 22.7%; the rest without data) and in 37.5% of molecularly confirmed cases, mainly conductive; in the French cohort, 1 of 5 assessed had sensorineural hearing loss [6, 36]. Postnatal growth was normal in 5 of 6 [6]. Neurodevelopment was normal in the 9 living patients of the French cohort, which included adults up to 46 years; in the review, normal cognition was confirmed in 54.5% and impaired in 11.4% (one case with perinatal hypoxia and microcephaly, four with mild speech or developmental delays) [6, 36]. One case of speech delay was accompanied by bilateral conductive hearing loss, suggesting an auditory contribution [6]. Three of the 44 patients in the review (6.7%) died in the first two weeks, two from confirmed respiratory failure [36].

3.4. Other types in the class

3.5. Comparison between Nager, Miller and Treacher Collins

Source: comparison from the 2025 systematic review [36].

3.6. Thauvin-Robinet-Faivre syndrome (FIBP)

Thauvin-Robinet-Faivre syndrome (TROFAS; OMIM 617107; ORPHA:500095) is an autosomal recessive overgrowth syndrome caused by biallelic variants of FIBP (11q13.1), the gene for the intracellular FGF1-binding protein [7, 56, 57]. It has no acrofacial dysostosis. The triad is generalised overgrowth (macrosomia and tall stature for age), developmental delay with learning difficulties or mild intellectual disability, and facial dysmorphism, generally with macrocephaly; Orphanet adds large hands and feet with large thumbs and halluces and spatulate digits [56, 57]. The first patient, the child of consanguineous parents, had overgrowth, macrocephaly, retinal coloboma, large thumbs, severe varicose veins and learning difficulties, with a homozygous nonsense variant; his fibroblasts proliferated more than controls [91]. Akawi and colleagues described three siblings with intellectual disability, moderate overgrowth and renal dysplasia, one with Wilms tumour, homozygous for an in-frame insertion (NM_004214.5:c.175_176insTAA, p.(His59delinsLeuAsn) in VariantValidator) [16, 92, 93]. Subsequent reports expanded the phenotype: sialorrhoea, recurrent pulmonary infections and chronic lung disease, hyperextensible elbows, hypoplastic nipples and cryptorchidism in a 4-year-old boy [57]; non-ossifying fibromas of the knees, bowing of the tibia, radius and ulna, subglottic tracheal stenosis, hypoplastic pulmonary artery with a non-functioning left lung, double-chambered right ventricle, ventricular septal defect, complete atrioventricular block with pacemaker implantation at 14 years and intermediate uveitis, in a girl compound heterozygous for c.1003C>T p.(Arg335*) and c.497_498del p.(Ser166*) [93]; and follicular thyroid carcinoma and mucoepidermoid carcinoma of the parotid in a 16-year-old girl with segmental overgrowth, homozygous for NM_004214.5:c.412-3_415dup [94]. This last variant was published in another report as NM_198897.2:c.415_416insCAGTTTG p.(Asp139AlafsTer3); on the MANE transcript, VariantValidator describes it as a duplication spanning the intron-exon junction, with an unpredictable protein effect (p.?) [16, 57]. Early-onset psychosis has also been described in a 24-year-old adult [93]. In a synthesis of 8 patients from 5 families, all had tall stature and developmental delay or intellectual deficit; macrocephaly in 6 of 8, cardiovascular, genitourinary and skeletal anomalies in 5 of 8 each, and ocular anomalies in 3 of 8 [95]. The first patient was the child of consanguineous North African parents and the three siblings of Akawi and colleagues of consanguineous Arab parents; in a family with two affected siblings, the heterozygous father had undergone nephrectomy for renal cell carcinoma [95]. Tumour predisposition (Wilms tumour, carcinomas) rests on isolated cases and has not been quantified [92, 94, 95].

3.7. Mandibulofacial dysostosis with microcephaly

The GeneReviews clinical description is based on 126 patients with a pathogenic EFTUD2 variant published up to 2019 [12]. These are published cases, biased towards classic and severe forms, and not a population-based cohort [27].

Face. The face is recognisable from early childhood: metopic ridge, prominent glabella, high and broad nasal root with a prominent bridge and bulbous tip, large mouth, everted lower lip and, frequently, facial asymmetry; the palpebral fissures may be upslanting or downslanting, unlike the constant downslant of Treacher Collins syndrome [12, 60]. The pinna has a deficiency of the upper helix and antihelix and, sometimes, a right-angled (“squared”) posteroinferior border of the lobule, a suggestive sign [12]. A cleft of the zygomatic arch was found in 10 of 19 patients studied by computed tomography with three-dimensional reconstruction [12]. The facial phenotype changes with age and remains identifiable in adults [27, 96].

Growth and neurodevelopment. Microcephaly may be congenital or postnatal, with marked deceleration of head growth in the first year; some patients catch up and reach adulthood with a normal head circumference, so old growth charts should be reviewed in a normocephalic adult, and patients with normal head circumference and intellectual disability have been described [12, 27, 60]. Syndrome-specific head circumference and height charts exist [27]. Independent walking appeared, on average, at 26 months (13–60 months; n = 38) and, in verbal patients, first words at 27 months (12 months to more than 5.5 years; n = 32); Smith states that only half of patients acquire oral language, and assessment of language is confounded by hearing loss and cleft palate [12, 27, 60]. Of the adults in the 2016 series, one was under state guardianship, four lived with their parents, one in a group home and two in their own home or with a spouse; at least one had simple paid work and another completed secondary education, while others were non-verbal and dependent in daily activities, with behavioural disorders [27]. There are no long-term neuropsychological studies [12]. The epilepsy has not been characterised; febrile seizures and a patient with recurrent seizures and right frontal spikes on electroencephalography have been described [12, 60]. Magnetic resonance imaging shows delayed myelination and non-specific white matter changes in about half of patients; reduced gyration, cerebral atrophy, cerebellar and pontine hypoplasia, agenesis of the olfactory bulbs and one case of exencephaly are rare [12, 60].

Ear and hearing. Hearing loss is mainly conductive: about 60% in GeneReviews; 50% conductive, 10% sensorineural and 25% mixed in Smith. It results from malformation or absence of the ossicles and atresia of the canal, and temporal bone tomography shows dysplastic or absent ossicles and hypoplasia of the semicircular canals and vestibule [12, 27, 60].

Extracranial malformations. Oesophageal atresia is generally type C (blind upper pouch and distal tracheo-oesophageal fistula) and may be associated with tracheomalacia and posterior laryngotracheo-oesophageal clefts [12]. Besides septal defects, tetralogy of Fallot, patent ductus arteriosus and aortic arch anomalies, such as coarctation, have been described [12, 60]. Less commonly there is unilateral renal agenesis, vesicoureteric reflux, pelviureteric junction obstruction, cryptorchidism, lacrimal duct anomalies, epibulbar dermoid, reduced mouth opening, absent 12th pair of ribs and laryngeal cleft [12, 27]. In 2026 the first association with congenital diaphragmatic hernia was described, in a late preterm newborn girl with a de novo variant [97].

Natural history. Prenatal presentation with polyhydramnios and severe micrognathia is occasional; a minority of patients have critical airway obstruction requiring endoscopic assessment and surgery, and feeding problems stem from the airway and cleft palate [60]. In a French series of 36 patients, Lehalle and colleagues considered the entity probably more frequent than Nager and Miller syndromes, as it had been underdiagnosed under other labels [96].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Prenatal suspicion arises with severe micrognathia associated with short upper limbs or limb defects, sometimes with polyhydramnios [35, 98]. In a Japanese case, observation of short upper limbs on two- and three-dimensional ultrasound led to a search for micrognathia, and fetal magnetic resonance imaging and three-dimensional computed tomography allowed diagnosis before birth [98]. The Rodríguez form was identified on ultrasound at 20 and 24 weeks, through the severity of the upper limb defects and the involvement of the lower limbs [99]. Even so, ultrasound has low sensitivity for bone defects: among about 100 published cases of Nager syndrome, only 10 had a prenatal diagnosis, and in the case in section 10 the scans showed only a relatively high amniotic fluid index and slow growth of the biparietal diameter from 32 weeks [46, 51]. In Miller syndrome, limb and/or cardiac anomalies were detected on ultrasound in 4 of 7 pregnancies in the French cohort; the combination of absent digits of the ulnar or fibular ray, mesomelia, radioulnar or carpal/tarsal synostosis and heart disease should raise suspicion even before the mandibulofacial dysostosis is evident [6].

4.2. Newborn

The signs that should suggest an acrofacial dysostosis are a Treacher Collins-type face (malar hypoplasia, downslanting palpebral fissures, micrognathia, ear malformation) associated with any limb anomaly, however subtle [44, 50]. The Oxford Desk Reference recommends, in the presence of ear anomalies, looking for malar hypoplasia (Treacher Collins, Nager, Miller), measuring head circumference (microcephaly suggests EFTUD2) and examining the limbs: radial ray anomalies suggest Nager, ulnar ray anomalies suggest Miller, triphalangeal or hypoplastic thumbs suggest Townes-Brocks and thumb duplication or deficiency also occurs in the oculo-auriculo-vertebral spectrum [50]. With radial ray defects, malar hypoplasia and micrognathia point towards Nager [100]. Eyelid coloboma appears in Treacher Collins, Nager and the oculo-auriculo-vertebral spectrum [101]. A subtle preaxial anomaly, such as a first web space contracture with a poorly mobile thumb, may go unnoticed and lead to a misdiagnosis of Treacher Collins [51].

4.3. Emergency signs

Upper airway obstruction at birth is the main emergency: 91% of newborns with Nager syndrome in the North American neonatal cohort were intubated at birth, and intubation may be impossible because of micrognathia, requiring immediate tracheostomy [87, 98]. Signs of obstruction during sleep, feeding difficulties, aspiration and faltering growth require airway assessment and a sleep study [44, 102]. Corneal exposure due to lagophthalmos or coloboma requires immediate eye protection [44]. In Miller syndrome, neonatal cholestasis and heart defects should be sought [6, 41].

4.4. Later ages

In older children and adults, an old clinical diagnosis of Treacher Collins, Nager or Miller syndrome without molecular confirmation should be reviewed with current tests, especially before reproductive decisions [36, 44]. Language delay in a child with these syndromes should first prompt assessment of hearing [6, 44]. The sources consulted do not describe newborn screening programmes for these entities, and the European consensus calls for audiological assessment soon after birth [44].

4.5. Mandibulofacial dysostosis with microcephaly

This entity should be considered with mandibulofacial dysostosis associated with microcephaly, intellectual disability or developmental delay, typical pinna malformation or hearing loss [12]. In the newborn, inability to pass a nasogastric tube, unexplained respiratory difficulty or polyhydramnios in pregnancy require urgent assessment for oesophageal atresia, and choanal atresia and micrognathia may necessitate intubation or tracheostomy [12]. The combination of oesophageal atresia with microcephaly and ear anomalies points to EFTUD2, alongside Feingold and CHARGE syndromes [62, 103]. In an adult with intellectual disability, cleft palate and micrognathia without a diagnosis, exome sequencing may identify the variant decades later, as in a 23-year-old man with autism spectrum disorder, microcephaly and conductive hearing loss, with previous negative studies (fragile X, microarray, FISH and subtelomeres) [84].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no validated formal diagnostic criteria for any acrofacial dysostosis [36, 67]. The clinical diagnosis of Nager syndrome rests on the association of mandibulofacial dysostosis with preaxial upper limb defects, and that of Miller syndrome on the association with postaxial defects of all four limbs [2, 5]. The 2025 systematic review proposed a phenotypic checklist for Miller syndrome, and the European facial dysostosis registry defined 110 data elements for standardised assessment [36, 104]. The European consensus recommends that all patients with suspected facial dysostosis be referred to a clinical geneticist for phenotypic assessment and counselling [44].

5.2. Imaging and functional assessment

Radiographs of the skull and limbs document malar and mandibular hypoplasia and the limb defects (aplasia or hypoplasia of the thumb and radius, radioulnar synostosis, absent 5th rays, “Y”-shaped metacarpals, triangular terminal phalanges) [6, 39, 41]. Three-dimensional computed tomography helps with diagnosis and surgical planning, including models for custom implants, and CT of the zygomatic arch and TMJ is indicated when mouth opening is limited [44, 46]. The initial assessment includes audiology, echocardiography, a sleep study and ophthalmological examination [44, 67].

5.3. Biomarkers in Miller syndrome

Dihydroorotate accumulates in plasma and urine and may serve as a biochemical screen [41]. In a 4-year-old boy, liquid chromatography with tandem mass spectrometry showed markedly raised dihydroorotate in urine and plasma, also detectable in dried blood and plasma spots, with raised orotic acid in urine but undetectable in plasma; dihydroorotate did not degrade spontaneously to orotic acid over 60 hours, indicating enzymatic oxidation during renal secretion [45]. In two other patients with variants, urinary orotic acid was raised without an increase in dihydroorotate [65]. A normal urinary dihydroorotate does not exclude the diagnosis, reference values have not been published for clinical use and the test is not a validated diagnostic assay [77, 78]. Enzymatic assays and yeast complementation are research tools for interpreting missense variants [65].

5.4. Molecular tests

The European consensus accepts several strategies: a targeted panel (TCOF1, POLR1B, POLR1C, POLR1D, SF3B4, DHODH) by next-generation sequencing, including in silico panels on exome or genome, and RNA analysis in selected cases [44]. Targeted tests are preferred when the phenotype is typical; exome or genome when the phenotype is atypical, when there are features suggesting another syndrome or when earlier tests were negative [44]. In patients with Nager syndrome without an SF3B4 variant, Marszałek-Kruk and colleagues suggest studying TCOF1, POLR1D, POLR1C, POLR1B, DHODH and EFTUD2 [46]. The case in section 10 illustrates the risk of a restricted panel: the Treacher Collins panel was negative and only the extended reanalysis identified the SF3B4 variant [51].

5.5. Limits of the tests

A proportion of patients with a clinical diagnosis of Nager syndrome remain without a molecular diagnosis, and the proportion of detectable variants in a gene does not equate to the clinical sensitivity of the test, because it depends on the accuracy of the initial clinical diagnosis [22, 53]. In Miller syndrome, only 18.2% of published cases had molecular confirmation, so some of them may correspond to other entities [36]. Exome sequencing may miss exon deletions, deep intronic variants, repeat expansions and low-level mosaicism; somatic and germline mosaicism have been implicated in these syndromes and should be considered in counselling [21, 44]. A variant of uncertain significance neither confirms nor excludes the diagnosis, and family segregation and functional studies may help to reclassify it [12, 69].

5.6. Report content

The report should state the gene, the reference transcript with version (NM_005850.5 for SF3B4, NM_001361.5 for DHODH), HGVS nomenclature at the cDNA and protein levels, the genomic coordinate with the genome build, the zygosity and the classification according to ACMG/AMP criteria [16, 51]. In the case in section 10, the variant c.1A>G was classified as pathogenic with the criteria PVS1 (moderate), PS4, PM2, PM6, PP1 and PP4 [51]. Variants described on old transcripts should be reconverted to the MANE transcript; in Thauvin-Robinet-Faivre syndrome, for example, the same FIBP alteration appears as an insertion with frameshift on one transcript and as a duplication at the intron-exon junction on the MANE transcript [16, 94].

5.7. Algorithm

1. Newborn or fetus with mandibulofacial dysostosis: stabilise the airway and examine the limbs (radius and thumb, ulna and 5th digit, fibula, tibia), head circumference, heart and choanae [44, 50].
2. Preaxial defects without microcephaly: SF3B4 with copy number analysis, ideally in a facial dysostosis panel [44, 67].
3. Postaxial defects (5th ray, ulna, fibula): DHODH; plasma dihydroorotate as support, without exclusion value [44, 45].
4. Microcephaly, oesophageal atresia or intellectual disability: consider EFTUD2; choanal atresia with eyelid coloboma: TXNL4A with promoter study; median mandibular cleft with radial and ulnar defects: EIF4A3 [11, 12, 33].
5. Abnormal neurodevelopment, heart disease and bowed long bones: include POLR1A [37].
6. Negative: exome or genome with CNV analysis and, if possible, RNA; maintain the clinical diagnosis and reassess periodically [44, 75].

5.8. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible; without a molecular diagnosis they are not, and the European consensus recommends more detailed ultrasound in subsequent pregnancies [44]. Chromosomal microarray detected SF3B4 deletions in a 12-week fetus and in another in the second trimester [67, 70]. Fetal exome sequencing identified SF3B4 variants in fetuses with the Rodríguez form [21]. When a facial dysostosis is suspected prenatally, the pregnant woman should be referred to a specialised obstetric unit to plan the delivery, given the risk of respiratory obstruction [44, 98].

5.9. Diagnosis of mandibulofacial dysostosis with microcephaly

The diagnosis is established in a proband with typical signs and a heterozygous pathogenic or likely pathogenic variant in EFTUD2; a variant of uncertain significance neither confirms nor excludes the diagnosis [12]. There are no validated formal clinical criteria; GeneReviews considers suggestive mandibulofacial dysostosis associated with microcephaly (head circumference ≤ −2 SD, congenital or postnatal), intellectual disability, characteristic pinna malformations or hearing loss, generally conductive [12].

In a characteristic phenotype, targeted testing (single gene or panel with deletion/duplication analysis) is the first choice; in an atypical phenotype, exome or genome [12]. Sequencing detects 93% of known pathogenic variants and gene-targeted deletion/duplication analysis the remaining 7% [12]. Huang and colleagues estimated that the combined sensitivity of these methods approaches 100% in patients with a typical phenotype; this proportion refers to the variants detectable in confirmed cases and does not replace clinical sensitivity, which depends on the rigour of the initial clinical diagnosis [27]. Chromosomal microarray detects the 17q21.31 deletions that include the gene and neighbouring genes and is the first test in a fetus with structural anomalies; when it is normal, exome sequencing follows [38, 62, 85]. Computed tomography with three-dimensional reconstruction documents the cleft of the zygomatic arch, and that of the temporal bone the ossicular and inner ear malformations [12].

Sanger sequencing poorly detects mosaicism below 15–20% variant alleles. In the case of Wang and colleagues, the first study did not detect the variant in the mother and only repetition on a fresh sample showed low-level mosaicism; the authors propose digital PCR or high-depth next-generation sequencing (more than 500×) and the study of other tissues (hair roots, urine, buccal mucosa) in the parents of a patient with an apparently de novo variant [38]. Leucocyte DNA testing may not detect somatic mosaicism [12].

The sensitivity of prenatal ultrasound has not been assessed, and molecular testing is the recommended method when the familial variant is known [12]. In the review by Wang and colleagues, micrognathia was the most frequent prenatal finding (6 of 9 fetuses with recorded gestational age), followed by polyhydramnios (10 of 27) and a small or non-visualised stomach (5 of 11); microcephaly was recognised in the prenatal period in 16 of 35 patients, probably because it appears late in gestation [38]. Kucińska and colleagues described two Polish fetuses with complete Robin sequence, V-shaped posterior cleft palate and central nervous system anomalies (cavitations of the thalamic eminences and cerebellar diameter below the 5th centile in one, agenesis or severe dysplasia of the corpus callosum with absent septum pellucidum in the other), and proposed these anomalies as a clue for the differential diagnosis with Treacher Collins and CHARGE syndromes [85]. These findings are not specific: polyhydramnios and micrognathia are more often associated with aneuploidies and copy number variants, so microarray or low-coverage sequencing for copy number variants precedes exome sequencing [38].

6. Differential Diagnosis

6.1. Principles

The differential diagnosis is organised along three axes: the presence or absence of mandibulofacial dysostosis, the topography of the limb defects (preaxial, postaxial, transverse, phocomelia) and extracraniofacial signs pointing to another mechanism, such as microcephaly, oesophageal atresia, choanal atresia, anaemia or vertebral anomalies [12, 36, 50]. Treacher Collins syndrome is the most frequent misdiagnosis of Nager syndrome, and only the limbs distinguish them [51, 76].

6.2. Nager versus Treacher Collins

The face may be indistinguishable: malar hypoplasia, downslanting fissures and micrognathia occur in both [76]. The differences are the limb defects, present in all patients with Nager syndrome and rare in Treacher Collins, the higher frequency of cleft palate in Nager (77.8% versus 25.3% in confirmed cases) and lower eyelid coloboma, typical of Treacher Collins [36]. Micrognathia in Nager tends to be more severe, with a greater need for intubation and tracheostomy and higher neonatal mortality [87]. A subtle thumb defect should be actively sought [51].

6.3. Nager versus Miller

The classic criterion is topography: preaxial (thumb, radius) in Nager, postaxial (5th digit, ulna, fibula) in Miller, which also affects the lower limbs [39, 50]. The French cohort showed frequent preaxial involvement in Miller (6 of 9), and in Nager there are foot anomalies in more than half of patients, so the clinical distinction is imperfect and the molecular diagnosis decides [1, 6]. Ectropion, cup-shaped ears, accessory nipples and rare microtia favour Miller; hearing loss is more frequent in Nager [4, 36]. DHODH was sequenced in 12 patients with Nager syndrome without pathogenic variants [23].

6.4. Nager versus mandibulofacial dysostosis with microcephaly

Microcephaly, intellectual disability, oesophageal atresia and cleft of the zygomatic arch point to EFTUD2; head circumference and intelligence are normal in Nager [12]. A patient in the SF3B4 discovery cohort, negative for this gene, had an EFTUD2 variant and microcephaly [1].

Before the gene was identified, many patients with EFTUD2 variants had been diagnosed with Feingold syndrome, CHARGE syndrome or oculo-auriculo-vertebral spectrum with oesophageal atresia, and at least two had been classified as bilateral oculo-auriculo-vertebral spectrum; conversely, no EFTUD2 variants were found in series of isolated oesophageal atresia or isolated oculo-auriculo-vertebral spectrum [12, 62]. Midline cleft palate is typical of mandibulofacial dysostosis with microcephaly, whereas craniofacial microsomia may have any type of orofacial cleft, including lateral clefts; vertebral anomalies suggest craniofacial microsomia [12].

6.5. Rodríguez versus other lethal forms

The Rodríguez form is distinguished from classic Nager and from Miller by the severity of the upper limb defects, the involvement of the lower limbs and the absence of eyelid coloboma and accessory nipples, but it belongs to the SF3B4 spectrum [40, 99]. Roberts syndrome, with severe symmetrical limb shortening, is the main skeletal differential diagnosis [39, 100].

7. Treatments and Risk Management Strategies

7.1. Framework and evidence

No acrofacial dysostosis has a treatment directed at the molecular defect, and there are no clinical trials registered on ClinicalTrials.gov for Nager syndrome, Miller syndrome or the acrofacial dysostoses (search of 29 October 2026; the only records found concern fixation devices or generic craniofacial surgical techniques) [107]. Management is multidisciplinary, staged and extends from birth to about 20 years of age [46]. The only structured recommendation is the European clinical consensus for facial dysostoses (Treacher Collins, Nager and Miller syndromes), developed in 2024 by ERN CRANIO experts using the Delphi method: 92 professionals from 13 centres in 9 countries and 3 patient representatives, three voting rounds and consensus defined as a mean of at least 7 on a scale of 1 to 9 with at most one outlier [44]. The evidence base is observational and of low quality, the literature on Miller syndrome comprises about 40 cases and only two experts voted on the statements on limb anomalies, so the recommendations for the limbs and for Miller syndrome should be read with caution [44]. The consensus considers that craniofacial reconstruction may follow similar principles in the three syndromes, but that Nager and Miller require additional attention because of their frequent severity [44]. The classic surgical sequence begins with breathing and feeding, moves on to the oral and facial clefts, then to the eyelids and malar region, and ends with the nose and pinna [46, 67].

7.2. Organisation of care

The European consensus recommends a team with expertise in craniofacial reconstruction, airway, eyes and lacrimal drainage, speech, feeding and swallowing, dentistry and orthodontics, hearing, extracranial anomalies, psychology, cognition, genetics and coordination; when national expertise is insufficient, ERN CRANIO should be used [44, 48]. Marszałek-Kruk and colleagues also include the hand surgeon and the physiotherapist [46]. Parents should receive, at the outset and before each intervention, information on the expected consequences, the treatment plan, the goals, aftercare and complications, and be informed about patient associations [44]. Speech therapy and orthodontics may take place near the family's home, under the supervision of the reference centre [44].

7.3. Airway

Multidisciplinary assessment of all levels of obstruction should precede any intervention, and respiratory problems in the first year require complete examination of the airway [44]. Obstructive sleep apnoea should be screened for routinely, with polysomnography as the reference method; the Epworth and Brouillette questionnaires are not suitable, and there was no consensus on screening frequency, which should be higher when there are symptoms or faltering growth [44]. Airway endoscopy or drug-induced sleep endoscopy help to characterise the obstruction, and are recommended routinely in tracheostomised patients and those with severe apnoea, preferably under the same anaesthetic as other procedures [44]. In moderate or severe apnoea due to multilevel obstruction, non-invasive ventilation (continuous or bilevel positive pressure) or tracheostomy relieve symptoms before definitive correction [44]. Otorhinolaryngological assessment should exclude adenotonsillar hypertrophy, treatable by adenotonsillectomy; if this does not resolve the problem, mandibular distraction osteogenesis may relieve obstruction linked to micrognathia, with candidacy defined by endoscopy, videolaryngoscopy and clinical examination [44]. All levels of obstruction should be treated, apnoea may recur after successful distraction, and follow-up polysomnography should be performed at least 6 weeks after distraction; in tracheostomised patients, polysomnography is reliable only with the cannula capped [44].

Mandibular distraction is also used to avoid tracheostomy, in two stages (lengthening and repositioning), and may be repeated with growth [46]. The European consensus warns that the success and complications of distraction in growing patients with facial dysostoses are worse than in Robin sequence, that results should be assessed separately and that parents should be aware of all possible consequences [44]. In the North American neonatal cohort, newborns with mandibulofacial dysostosis underwent more tracheostomies and gastrostomies and fewer mandibular distractions than other forms of micrognathia (Treacher Collins: tracheostomy 54% versus 11%, distraction 9.7% versus 28.2%) [87]. In the series of Chummun and colleagues, 5 of 9 patients with Nager syndrome underwent mandibular advancement, 2 TMJ reconstruction and 1 genioplasty [76]. In the Finnish children, the proposed surgical target was the height of the mandibular ramus, the most deficient structure [34]. The international consensus on Robin sequence recommends sleep studies, because obstruction is intermittent and predominates during sleep, and points out the possibility of multilevel obstruction [102].

Tracheostomy and decannulation. The duration of tracheostomy is indeterminate and decannulation is not always possible or permanent [44]. It may be considered if the cannula can be capped during the day and if an in-hospital sleep study with the cannula capped and endoscopy show no significant obstruction, always after multidisciplinary discussion of swallowing safety, the results, ease of intubation and the family's preference [44]. One of the Polish patients required emergency tracheostomy at 7 years for respiratory failure, after several distractions [46].

Anaesthesia. An airway plan is needed before each induction, with staff and equipment for techniques other than direct laryngoscopy; the laryngeal mask airway is an alternative when the procedure allows it, and a “difficult intubation” card helps in emergencies [44].

7.4. Feeding, swallowing and growth

Feeding is provided by tube or gastrostomy when the oral route is not safe [35, 46]. The European consensus recommends routine screening for feeding problems (risk of aspiration), assessment by a speech and language therapist when suspected, early feeding training especially in children with gastrostomy or tracheostomy, and annual measurement of weight and length between 1 and 6 years, considering sleep apnoea and feeding problems as causes of poor growth [44]. The rehabilitation programme described by Marszałek-Kruk and colleagues includes oral desensitisation with progressively flavoured textures and liquids and training in all phases of feeding, from spoon to bottle [46].

7.5. Orofacial clefts

Cleft lip is treated according to the general cleft lip and palate guidelines [44]. Palatoplasty may be considered if the obstructive apnoea-hypopnoea index is 5 or less and there is no significant carbon dioxide retention, or if polysomnography is normal with or without a palatal plate; after closure there should be respiratory monitoring in intermediate care, and parents should know that closure may worsen breathing [44]. There is no reliable evidence on outcomes or on the ideal technique or age [44]. In the French Miller cohort, 4 patients required palatoplasty, while submucous clefts and bifid uvula did not [6].

7.6. Craniofacial reconstruction

Planning should be done by the team and the timing of each intervention individualised according to severity and functional problems (mouth opening, speech, feeding, breathing during sleep, eyelid closure, hearing) [44]. In maxillary and mandibular hypoplasia, counterclockwise correction improves facial projection and may open the posterior nasopharyngeal airway; counterclockwise distraction osteogenesis gives more palatal rotation than other techniques, and final orthognathic surgery is performed at skeletal maturity unless breathing requires it to be brought forward [44]. Orthodontics should precede mandibular surgery [46]. Autologous fat transfer (lipofilling or dermis-fat grafts) may improve contour, including in the infraorbital region to reduce ectropion [44]. Evidence on orbitozygomatic reconstruction techniques is insufficient and experts are divided; if bony reconstruction is chosen before maturity, deferring it to 6 to 12 years reduces resorption [44]. Marszałek-Kruk and colleagues place midface reconstruction with bone grafts or malar implants at about 16 years [46]. 3D assessment (photogrammetry, MRI or CT) and patient-reported outcome measures are recommended to assess results [44].

Temporomandibular joint. When other options fail, total TMJ prosthesis may restore function, with planning by three-dimensional CT [44]. The first total joint replacement in Nager syndrome was described by Opitz and colleagues in 2000 [46]. After release of an ankylosis, rehabilitation should begin on the first day: physiotherapy twice a day as an outpatient and every 2 hours at home, with wedges between the teeth for about 1 hour, after analgesia [46].

Eyelids. There is insufficient evidence to choose techniques; lower (pseudo)colobomas may improve with a dermis-fat graft and subperiosteal malar elevation with upper eyelid flaps; lagophthalmos with exposure keratopathy requires protective ointment and occlusion and, depending on exposure, surgery; ptosis or blepharophimosis threatening vision is corrected early, with orthoptic follow-up; without functional consequences, eyelid surgery has no critical age and is performed after periorbital surgery [44].

Pinna. The principles of the European craniofacial microsomia guideline are followed, with costal cartilage or synthetic implants and osseointegrated implants after failure; reconstruction should be coordinated with the placement of implantable hearing devices and is mainly aesthetic [44, 46].

7.7. Hearing, speech and language

Audiological screening should be performed soon after birth and repeated, with otological and audiological assessment, at least every 3 years, even with minor ear malformations [44]. Air conduction hearing aids are the first choice if the anatomy allows; in conductive or mixed hearing loss due to malformation, bone conduction devices (on a softband, adhesive or implantable), active middle ear implants and passive or active transcutaneous devices are used [44]. Reconstructive surgery of the middle ear or canal has no demonstrated benefit and bone conduction devices are preferred; audiometry should be repeated 4 weeks after fitting [44]. In the Polish series, one patient received a bone conduction device and another a hearing implant [46].

Speech should be assessed from the pre-verbal stage and screened at 2 years; the causes are multiple (cleft, narrow airway, malocclusion, velopharyngeal insufficiency, tracheostomy, hearing loss) and follow-up may last into adulthood [44]. Velopharyngeal insufficiency may be treated with double buccal myomucosal flaps, weighing the risk of apnoea, after assessment by videofluoroscopy and nasendoscopy [44].

7.8. Eyes and oral health

The initial ophthalmological examination looks for colobomas, lagophthalmos, lacrimal drainage anomalies, refractive errors and strabismus; follow-up monitors refraction, strabismus, ptosis, epiphora, exposure keratopathy and amblyopia, with at least one examination after craniofacial surgery [44]. Epiphora is treated conservatively if mild and, if severe, with punctoplasty, balloon dacryoplasty, dacryocystorhinostomy or conjunctivodacryocystorhinostomy [44]. In Miller syndrome, the finding of optic atrophy in one family justifies examination of the optic nerve [6]. Dental visits should be six-monthly, because of dry mouth, mouth breathing and a soft diet, with at least one clinical or radiological screen for dental anomalies and orthodontic monitoring of growth [44].

7.9. Limbs

Limb anomalies justify prompt referral to a specialised centre [44]. If the thumb is present but unstable, it may be stabilised and strengthened by tendon or muscle transfer; if it is absent or unstable, pollicisation of the index finger is performed [46]. Chummun and colleagues advocate early pollicisation to avoid lasting impairment of manual dexterity; in their series, 4 patients underwent pollicisation, 2 had excision of supernumerary radial digits and 1 had correction of thumb duplication [76]. In Miller syndrome, interventions include excision of non-functional rudimentary digits, such as a 5th finger attached by a skin bridge [6]. Physiotherapy and occupational therapy should begin early and accompany all phases of motor development [46].

7.10. Extracranial anomalies and psychology

The consensus calls for screening for vertebral anomalies (spina bifida occulta, dysmorphic vertebrae, reduced intervertebral space, scoliosis, pectus) and cardiac anomalies (atrial or ventricular septal defect, ductus arteriosus) in all newly diagnosed patients [44]. In Miller syndrome, echocardiography is considered essential [6]. Psychological support includes family consultations on motivations and expectations of surgery, support for parents, cognitive assessment when in doubt, play therapy before procedures and screening for anxiety and psychological trauma after life-threatening situations [44].

7.11. Drugs

There are no drugs approved for any acrofacial dysostosis [107, 108]. In Miller syndrome, supplementation with uridine or orotic acid could, in theory, bypass the enzymatic block, but Saudubray considers efficacy unlikely, because the main damage occurs in utero [78]. The only described use is a 3-month trial of oral uridine in a 4-year-old boy, for behavioural problems: plasma dihydroorotate fell, but the behavioural problems did not appear to resolve [45]. The abstract of the report does not state the formulation or the dose.

Uridine triacetate (Xuriden®) is the only uridine replacement medicine with a regulatory label consulted, and serves only as a comparison; its use in Miller syndrome would be off-label and without demonstrated benefit [45, 109].

Commonly used drugs (analgesics, antibiotics, anaesthetics, ocular lubricants) follow the usual indications for each clinical situation.

7.12. Trials and developments (up to October 2026)

There are no ongoing or completed interventional clinical trials for these syndromes [107]. The developments of the last 12 months are observational and preclinical studies. At the level of observational clinical studies: the French cohort of 10 patients with Miller syndrome (published online in July 2025), the systematic review of 44 Miller cases (2025), the North American neonatal cohort of Treacher Collins and Nager (2025) and the ERN CRANIO European facial dysostosis registry, with 110 data elements defined by Delphi (2025) [6, 36, 87, 104]. At the preclinical level: PTBP3, in the 9q32 region, was proposed as a candidate gene for Nager syndrome without an SF3B4 variant, based on Xenopus embryos [75]; a 2026 review synthesised the cellular and animal models and identified induced pluripotent stem cells and strategies to restore splicing as future directions, without human data [66]. Also described, without demonstrated clinical effect, were spliceosome gene variants in non-syndromic orofacial clefts and variants in TCOF1, POLR1B and DHODH in a child with congenital TMJ ankylosis [74, 112]. No company announcements, regulatory submissions or opinions were identified [107, 108].

7.13. Special populations

Pregnancy with an affected fetus. Prenatal suspicion justifies referral to a specialised obstetric unit and planning of delivery with a team prepared for a difficult airway, including immediate tracheostomy [44, 98].

Affected women. The sources consulted do not describe pregnancies in women with Nager or Miller syndrome; anaesthetic assessment before delivery follows the difficult airway plan [44]. DHODH inhibitors and methotrexate are associated with embryopathies similar to Miller syndrome [23, 110].

Perioperative care. Each anaesthetic requires an airway plan; procedures should be grouped to reduce the number of anaesthetics [44].

Transition. Final orthognathic surgery, midface reconstruction and nasal and ear surgery take place in adolescence and early adulthood, and speech therapy may extend beyond this; dental care is lifelong [44, 46].

7.14. Thauvin-Robinet-Faivre syndrome

There is no specific treatment or guideline; the reports recommend multidisciplinary management and prolonged follow-up, with cardiac (serial echocardiography and electrocardiography, because of the risk of atrioventricular block), respiratory, renal, ophthalmological and oncological assessment [92, 93]. Tumour predisposition (Wilms tumour, thyroid and parotid carcinomas) is based on isolated cases and there is no validated surveillance protocol [92, 94].

7.15. Mandibulofacial dysostosis with microcephaly

There are no published management guidelines or targeted treatment; the GeneReviews recommendations derive from clinical experience [12]. The 2024 European consensus is limited to Treacher Collins, Nager and Miller syndromes, so applying its airway, hearing and craniofacial surgery recommendations to this entity is an extrapolation [44].

In the newborn with airway compromise, intubation or tracheostomy stabilises the situation; craniofacial management is individualised by a team of oral and maxillofacial surgery, plastic surgery, otorhinolaryngology, dentistry and orthodontics, occupational therapy and speech therapy [12]. Oesophageal atresia, heart defects, renal anomalies and thumb anomalies are treated as outside the syndrome [12]. Hearing loss is treated with conventional hearing aids, bone conduction devices or cochlear implants, according to type and anatomy, and early intervention improves development [12, 60]. Short stature is managed expectantly and the response to growth hormone has not been described [12].

Early intervention (occupational therapy, physiotherapy, speech and feeding therapy), assessment for augmentative and alternative communication in patients with expressive language deficits, which does not delay speech, and the behavioural interventions used in autism spectrum disorder, when indicated, complete the plan; oromotor dysfunction is assessed at each visit, with a swallowing study if there is choking, faltering growth or recurrent respiratory infections, and a nasogastric tube or gastrostomy in severe cases [12]. There is no targeted drug and no clinical trial registered on ClinicalTrials.gov; antiepileptic drugs and other symptomatic drugs follow general indications [12, 107]. p53 inhibition in the mouse model and the proposal to increase expression of the normal allele are preclinical hypotheses, without human studies [27, 82]. Surveillance is set out in the table in section 11.2.

8. Reproductive Options and Family Counselling

8.1. Nager syndrome and the Rodríguez form

Inheritance is autosomal dominant [22, 35]. Most cases are sporadic and result from de novo variants: 4 of 4 cases with parental DNA in the series of Czeschik and colleagues and the case in section 10 [51, 53]. There is also transmission from mildly affected parents, sometimes recognised only after the diagnosis of a severely affected child; families with father-to-son, mother-to-son and four-generation transmission have been described [1, 15, 22]. Therefore, before concluding that a variant is de novo, the parents should be examined and tested [22, 44].

8.2. Miller syndrome

Inheritance is autosomal recessive: in a carrier couple, each child has a 25% probability of being affected, 50% of being a carrier and 25% of inheriting neither variant; all parents tested in the founding article were carriers [4, 23]. Recurrence in twins from a second pregnancy was described by Chrzanowska and Fryns [4]. In a consanguineous French family, the high frequency of the variant in the lineage produced patients in several generations, mimicking dominant inheritance (pseudodominance); apparently vertical inheritance in a family with Miller syndrome should therefore not lead to DHODH being excluded [6]. The risk for the children of an affected person depends on the carrier status of the partner and is higher in consanguineous unions [6].

8.3. Other entities

The Cincinnati type is autosomal dominant, with incomplete penetrance: of the 18 patients of Smallwood and colleagues, 7 had de novo variants, 7 inherited ones (5 from a parent without recognised signs) and 4 of undetermined origin [90]. Biallelic POLR1A variants cause hypomyelinating leukodystrophy, with its own counselling [24, 47]. Richieri-Costa-Pereira syndrome is autosomal recessive, with 36% recurrence in siblings and cousins and consanguinity in 44% of the Brazilian families studied [11]. Burn-McKeown syndrome is autosomal recessive, with risks of 25%, 50% and 25% for siblings [33]. Mandibulofacial dysostosis with microcephaly is dominant, almost always de novo, with a 50% risk when a parent is a carrier [12]. The Catania type is dominant (autosomal or X-linked) and Kennedy-Teebi presumably recessive [26, 49]. In Thauvin-Robinet-Faivre syndrome, which is recessive, the parents are obligate carriers and each sibling has a 25% risk [57, 93].

8.4. Cascade testing, prenatal and preimplantation diagnosis

The European consensus recommends genetic counselling for all parents planning a new pregnancy, with discussion of recurrence risk, prenatal diagnosis and preimplantation genetic testing [44]. These are possible only with the familial variant identified; without it, detailed ultrasound scans are offered [44]. Targeted testing of relatives of a confirmed patient is indicated even without typical facial features, because of intrafamilial variability and reduced penetrance [44]. In the case in section 10, the parents did not carry the variant and later had a healthy child [51]. Prenatal detection of an SF3B4 deletion by microarray at 12 weeks and in the second trimester shows that this test is useful when there are ultrasound anomalies [67, 70].

8.5. Minors and asymptomatic relatives

In Nager syndrome, an asymptomatic relative with the variant may transmit a severe form, which gives testing of siblings and parents reproductive relevance [22, 44]. In Miller syndrome, carrier testing of asymptomatic minor siblings has no immediate clinical utility; the sources consulted do not address this question specifically [44].

8.6. Mandibulofacial dysostosis with microcephaly

Inheritance is autosomal dominant. Among the 64 patients with parental studies in the 2016 series, the variant was de novo in 48 (75%), inherited from an affected parent in 12 (19%) and the result of proven germline mosaicism in 4 (6%; two sibling pairs with confirmed paternity and normal parental sequencing) [27]. Transmitting parents frequently had a milder phenotype, sometimes limited to facial asymmetry or a zygomatic cleft, so a negative family history is confirmed only by molecular testing of both parents [12, 14]. When a parent has the variant, the risk for each sibling is 50%, with unpredictable severity; when the variant is not found in the parents' blood, the risk remains above that of the general population, because of germline mosaicism; each child of an affected person has a 50% probability of inheriting the variant [12]. The case of Wang and colleagues illustrates the problem: a variant reported as de novo in the second fetus recurred in the third, and only repeating the study detected low-level maternal mosaicism; the authors advised preimplantation genetic testing or early prenatal diagnosis (section 10.4) [38]. Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known, but do not predict severity [12]. Counselling should be offered before pregnancy to the parents of patients and to young adults who are affected or at risk [12].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

The only population estimate for Nager syndrome comes from Finland: 3 patients diagnosed over 17 years, which the authors converted into an incidence of 3 per 1,000,000; Orphanet records it as a birth prevalence of 0.3 per 100,000 and classifies point prevalence as unknown [2, 34]. This is a small number of cases in a single country, which should not be generalised [34]. The literature contains about 100 cases of Nager syndrome, and Orphanet records 13 cases of the Rodríguez form [3, 35]. The 2025 review of Miller syndrome found 44 cases (56.8% from Europe, 20.5% from North America, 9.1% from Oceania, 6.8% from South America, 4.5% from Asia and 2.3% from Africa), with a slight male predominance (56.8%) and only 8 molecularly confirmed; the French cohort added 10 patients from France, Italy and Morocco [6, 36]. The geographical distribution of published cases reflects the origin of the publications and does not measure frequency by region [36]. Orphanet classifies the prevalence of Miller syndrome and the other forms as below 1 per 1,000,000 [5, 8–10]. Mandibulofacial dysostosis with microcephaly has at least 126 cases and Burn-McKeown syndrome 20 [12, 33].

9.2. Populations with a founder effect

Richieri-Costa-Pereira syndrome is the example of a founder effect in the class: 14 of the 15 families studied by Ferreira de Lima and colleagues were Brazilian, the series of Favaro and colleagues gathered 28 patients from 25 Brazilian families with 20 years of follow-up, and one Brazilian patient was the daughter of second cousins of Portuguese ancestry; the first case outside Brazil was described in France in 1999 [11]. The 16-repeat EIF4A3 allele was found in homozygosity or compound heterozygosity in practically all Brazilian patients tested [19]. The Catania and Palagonia types were described in families from the same small locality in Sicily [25].

9.3. Portugal and Brazil

Besides Richieri-Costa-Pereira syndrome, the sources consulted include Brazilian descriptions of Nager syndrome with thumb duplication (Giugliani and Pereira, 1984) and of Genée-Wiedemann syndrome (Pereira and colleagues, 1992; Richieri-Costa and Guion-Almeida, 1989) [1, 4]. The sources consulted do not provide epidemiological data from Portugal or Brazil for Nager and Miller syndromes.

9.4. Other populations

The neonatal cohort of US children's hospitals (2010–2023) and the Australian and Dutch, Polish and Finnish series are the main sources of natural history data [34, 46, 76, 87]. Isolated cases have been published from China, Japan, Georgia and Taiwan [46, 51, 98, 113].

9.5. European networks and patient associations

The relevant European network is ERN CRANIO (rare and complex craniofacial anomalies and ear, nose and throat disorders), coordinated from Rotterdam, which produced the clinical consensus and the European facial dysostosis registry [44, 48, 104]. The consensus recommends informing families about national and international patient associations [44]. Resources include the Foundation for Nager and Miller Syndromes (FNMS), an international support association listed by NORD, FACES (National Craniofacial Association, USA), Contact (United Kingdom) and the Pierre Robin Network [105, 114–116]. Representatives of Laposa and Rare Diseases Croatia took part in the consensus [44].

9.6. Mandibulofacial dysostosis with microcephaly

There is no population study. GeneReviews counted at least 126 patients with a confirmed variant, Wang and colleagues more than 170 published cases in 2025 and Kucińska and colleagues more than 160 in HGMD [12, 38, 85]. Orphanet classifies point prevalence as below 1 per 1,000,000 based on the 107 patients published up to 2016, which reflects the number of reports and not a measurement; the incidence of 1 per 1,000,000 cited by Kucińska and colleagues is not based on a population study in the sources consulted [13, 85]. Lehalle and colleagues considered the entity probably more frequent than Nager and Miller syndromes [96]. In the analysis of 156 published patients, the proportion of patients of European ancestry was higher than that of Asian patients, a difference that may reflect access to diagnosis and not true frequency [86].

The largest European series are French, with 10 and 36 patients, and German and multinational, with 8 patients; Polish fetal cases have been published [14, 62, 85, 96]. The first description is Brazilian, from Bauru, and a Brazilian centre took part in the 2016 update [27, 58]. In Portugal one case from Vila Nova de Gaia has been published (section 10.3) [83]. The patient resources listed by GeneReviews are the American Cleft Palate-Craniofacial Association, the Children's Craniofacial Association, the National Institute of Dental and Craniofacial Research and the World Craniofacial Foundation; the relevant European network is ERN CRANIO [12, 48].

10. Illustrative Clinical Case

10.1. Nager syndrome initially diagnosed as Treacher Collins

Zhao and Yang described a male newborn, born by vaginal delivery at 41 weeks, weighing 2995 g, 48 cm long, with a head circumference of 33 cm and an Apgar score of 10 [51]. Pregnancy ultrasound scans showed no craniofacial or limb anomalies; from 32 weeks a relatively high amniotic fluid index and slow growth of the biparietal diameter were recorded [51]. At birth he had bilateral and symmetrical malar hypoplasia, severe mandibular hypoplasia with retrognathia, maxillary protrusion, downslanting palpebral fissures, stenosed external auditory canals, a broad and high nasal root, macrostomia, a retracted tongue and posteriorly rotated dysplastic pinnae; the initial clinical diagnosis was Treacher Collins syndrome (figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC7521291/figure/jcla23426-fig-0001/) [51].

On the first day he had a haemoglobin of 226.0 g/L, haematocrit of 0.65 and total bilirubin of 104.3 µmol/L, and received phototherapy and dilution with normal saline [51]. On the second day nasal regurgitation of fluids and vomiting appeared, oral feeding could not be established, and gastric decompression and parenteral nutrition were started [51]. The parents declined further treatment and took the baby home, where he died a month later; three-dimensional post mortem computed tomography showed mandibular and malar hypoplasia [51].

The karyotype was normal and the TCOF1, POLR1D and POLR1C panel was negative. Extended reanalysis of the data (including DHODH, SF3B4 and EFTUD2) identified the heterozygous SF3B4 variant c.1A>G, which eliminates the initiation codon, confirmed by Sanger sequencing and absent from the parents [51]. On the MANE transcript it corresponds to NM_005850.5:c.1A>G, p.(Met1?), NC_000001.11:g.149927759T>C [16]. It was classified as pathogenic (PVS1 moderate, PS4, PM2, PM6, PP1, PP4) [51]. Only then were the photographs and a radiograph of the body reviewed and a first web space contracture and dysplasia of the right thumb and index finger recognised, which the parents had noticed as reduced thumb mobility (figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC7521291/figure/jcla23426-fig-0003/) [51]. Two years later the mother had a healthy son [51].

The case illustrates three points. The first is that the difference between Nager and Treacher Collins may lie in a subtle hand defect, which should be systematically sought [51, 76]. The second is that a panel restricted to the causes of Treacher Collins syndrome does not exclude an acrofacial dysostosis, which justifies the extended facial dysostosis panel or exome recommended by the European consensus [44, 51]. The third is that the refusal of treatment, a family decision described in the report, does not correspond to the recommended management: the European consensus provides for airway stabilisation, tube or gastrostomy feeding and multidisciplinary planning [44, 87].

10.2. Long-term surgical course

The Polish series of Marszałek-Kruk and colleagues illustrates the course under treatment [46]. Patient 1, a boy with an SF3B4 variant, had mandibular hypoplasia, low-set pinnae, atresia of the external auditory canal with bilateral conductive hearing loss and a vestigial thumb (figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC10815867/figure/genes-15-00029-f001/) [46]. He was tracheostomised in the neonatal period, underwent mandibular osteoplasty with distractors at 1 year, a further osteotomy with distractors at 2 years and bilateral osteodistraction at 5 and 7 years, required emergency tracheostomy for respiratory failure at 7 years and received a hearing implant [46]. Other patients in the series underwent up to four cycles of mandibular distraction, endoscopic gastrostomy at 7 years, a bone conduction device, pollicisation at 2 years and release of TMJ ankylosis with a fat graft at 3 years [46]. The repeated sequence of distractions and the late tracheostomy are consistent with the European consensus warning about the poorer results of distraction in growing patients with facial dysostoses [44].

10.3. Mandibulofacial dysostosis with microcephaly in a Portuguese newborn

Silva and colleagues, from Vila Nova de Gaia and Porto, described a 35-week newborn with intrauterine growth restriction, who required resuscitation at birth and was diagnosed on the first day with oesophageal atresia with tracheo-oesophageal fistula [83]. Examination showed a prominent forehead, plagiocephaly, low-set and malformed pinnae, hypertelorism, downslanting palpebral fissures, micrognathia, an everted lower lip, a short neck, widely spaced nipples and an inguinal hernia [83]. Imaging revealed inner ear dysplasia with agenesis of the vestibulocochlear nerves and global cerebral atrophy [83]. EFTUD2 testing identified the heterozygous variant NM_004247.4:c.831_832del p.(Lys277AsnfsTer7), not previously described [16, 83].

The case brings together the oesophageal atresia, ear malformation and micrognathia that point to EFTUD2, and shows that downslanting palpebral fissures, more typical of Treacher Collins syndrome, do not exclude this entity [12, 83]. Agenesis of the vestibulocochlear nerves has implications for auditory rehabilitation, because it conditions the indication for a cochlear implant [12, 83].

10.4. Recurrence due to maternal mosaicism

A 30-year-old Chinese woman, gravida 3, para 0, had had an early miscarriage and, in the second pregnancy, an ultrasound scan at 25 weeks showed facial asymmetry and a non-visualised stomach; after termination, exome sequencing of a fetal skin sample identified NM_004247.4:c.2444_2445del p.(Val815GlyfsTer69), which Sanger sequencing did not find in the parents' blood, and the recurrence risk was considered low [16, 38]. The woman's physical examination was normal and there was no family history [38]. In the third pregnancy, at the woman's request, amniocentesis was performed at 19 weeks and 4 days; scans at 12, 17 and 22 weeks were normal, but exome sequencing of the amniotic fluid showed the same variant, and repeat sequencing of maternal blood on a fresh sample revealed low-level mosaicism [38]. The pregnancy was terminated at 23 weeks and 3 days; the woman declined quantification of the mosaicism and was advised to use preimplantation genetic testing [38]. The case shows that a normal ultrasound does not exclude the disease and that a negative parental Sanger result does not exclude mosaicism [38].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

In Nager syndrome, risk is concentrated in the neonatal period: perinatal mortality of about 20% in the series gathered by Smith and in-hospital mortality of 27.3% in the 11 newborns admitted to neonatal intensive care in the USA between 2010 and 2023, with tracheostomy in 72.7% [35, 87]. These cohorts describe patients admitted to tertiary centres and may overestimate average severity [87]. After the neonatal period and childhood, the survival prognosis is good, but the need for repeated surgery, sleep apnoea and hearing loss accompany growth [46, 76]. The Rodríguez form is often lethal, although there are survivors with intensive treatment [3, 40]. Intelligence is generally normal [35].

In Miller syndrome, 3 of the 44 patients in the systematic review died in the first two weeks, mainly from respiratory failure; survivors generally have normal cognitive development, and the French cohort included adults up to 46 years without neurodevelopmental abnormalities [6, 36]. Ectropion and facial asymmetry may worsen with age, micrognathia tends to improve and neonatal cholestasis may progress to persistent liver disease [4, 41]. The sources consulted provide no life expectancy data for any of the entities.

In mandibulofacial dysostosis with microcephaly, prognosis depends, early in life, on the airway, oesophageal atresia and heart disease and, in the long term, on the intellectual disability, which ranges from mild to severe; there are adults with semi-independent lives and paid work and others who are totally dependent [12, 27]. The sources consulted provide no survival data for this entity.

11.2. Surveillance

12. Summary and Final Considerations

The acrofacial dysostoses combine a Treacher Collins-type face with limb defects, and the topography of these defects guides the diagnosis: preaxial in Nager syndrome, postaxial in Miller syndrome. Nager syndrome is due to haploinsufficiency of SF3B4, a spliceosome component, with dominant inheritance, most cases de novo and expressivity ranging from almost normal parents to the lethal Rodríguez form; about one quarter to two fifths of patients with a clinical diagnosis have no identified variant. Miller syndrome results from partial, biallelic deficiency of dihydroorotate dehydrogenase, an enzyme of pyrimidine synthesis, was the first Mendelian disease solved by exome sequencing and may mimic dominant inheritance in consanguineous families. The rare forms include the Cincinnati type (POLR1A), with neurodevelopmental abnormalities and heart disease, and Richieri-Costa-Pereira syndrome (EIF4A3), with a founder effect in Brazil and expansion alleles that escape conventional exomes.

The immediate risk is respiratory: in Nager syndrome most newborns are intubated at birth and many require tracheostomy, and neonatal mortality is higher than in Treacher Collins. Management follows the ERN CRANIO European consensus: a multidisciplinary team, an airway plan, screening for sleep apnoea by polysomnography, safe feeding, hearing assessed from birth and corrected preferably with bone conduction devices when there is malformation, staged craniofacial reconstruction up to skeletal maturity, early pollicisation when the thumb is absent, and ophthalmological, dental, cardiac and growth surveillance. There are no targeted drugs or clinical trials; uridine has been tested in a single patient with Miller syndrome without clinical benefit, and DHODH inhibitors reproduce the disease in animal models. Molecular diagnosis, by facial dysostosis panel with copy number analysis or by exome and genome sequencing, makes it possible to distinguish these syndromes from Treacher Collins and from mandibulofacial dysostosis with microcephaly and to provide reproductive counselling, including the possibility of gonadal mosaicism in Nager syndrome. Thauvin-Robinet-Faivre syndrome, sometimes associated with this class in indexes, is a recessive overgrowth syndrome due to FIBP variants, without acrofacial dysostosis, with heart disease, conduction block and possible tumour predisposition.

Mandibulofacial dysostosis with microcephaly, due to EFTUD2 haploinsufficiency, shares the Treacher Collins-type face and the spliceosomopathy mechanism of Nager syndrome, but is distinguished by microcephaly, intellectual disability and extracranial malformations such as oesophageal atresia, heart disease and thumb anomalies. It is autosomal dominant, almost always de novo, with parental germline mosaicism in 6% of the families studied, which calls for caution in counselling even when parental testing is negative.

13. References

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